Examining the dynamics and clinical relevance of Sox2+ cells in the Ptch1 heterozygous model of medulloblastoma

Medulloblastoma is the most common malignant pediatric brain tumour. Current therapies fail to provide those affected with quality and quantity of life, necessitating a greater understanding of the mechanisms driving growth. Previous studies in the irradiated Ptch1+/- model have postulated a growth hierarchy derived from rare, therapy-resistant, tumour-propagating cells that exhibit cardinal features of stemness. Utilizing the same model, I describe a direct role for Sox2 in conferring a stemness program in the tumour-propagating fraction. In an allograft model, I define a paradigm for combination therapy of both stem and progenitor cell-types using a transgenic ablative strategy in parallel with the Smoothened antagonist GDC-0449. I then provide evidence for proliferative heterogeneity within the Sox2+ compartment, identifying dividing and non-dividing cells as molecularly distinct cell states. These findings identify targeting Sox2+ cells as a requirement for disease cure and propose antagonizing the quiescent state may re-sensitize these cells to conventional therapies.M.Sc.2020-07-10 00:00:0